The invention relates generally to the field of non-competitive NMDA receptor antagonists that are analogs of phencyclidine (PCP). These compounds contain a polycyclic ring structure in place of the cycloalkyl ring of PCP, as well as an electron withdrawing group, hydroxyl or amino group at the para position of the phenyl ring. The antagonists disclosed herein are useful for ameliorating, treating, and preventing ailments associated with detrimental effects attributable to “over-activation” of NMDA receptors on cells of various types, such as over-excitation of neurons having NMDA receptors.
Neuronal damage, including brain damage, can occur via over-excitation of neurons. When over-excitation occurs, the membrane potential collapses and that can lead to cell death. The N-methyl-D-aspartate (NMDA) receptor appears to have a role in neurodegeneration that occurs by means of this mechanism. When over-activated, the NMDA receptor allows excess calcium ions (i.e., Ca2+) to flow into the neuron bearing the receptor, causing both necrosis and apoptosis of the neuron.
The NMDA receptor is a transmembrane protein located on neuronal cells and has multiple ligand binding sites, including sites for glutamate, glycine, polyamine and cations (e.g., Zn2+ and Mg2+) and phencyclidine (PCP) binding as shown schematically in FIG. 1.
Rogawski reports that NMDA receptor channel blockers may act as neuroprotective agents. As illustrated in FIG. 1, PCP acts as a non-competitive antagonist of the NMDA receptor by binding in the ion channel thereof and blocking the inflow of calcium ions into the neuron. However, PCP does not selectively interact with the NMDA receptor; PCP binds with other neuronal receptors, including sigma (σ) receptors and cholinergic (nicotinic) receptors. PCP also inhibits uptake of biogenic amines (including dopamine, norepinephrine and epinephrine) and interacts with voltage-gated potassium channels.
The multiple and various interactions and activities of PCP are thought to induce the well-known side effects of PCP ingestion, which include psychosis and ataxia. These side effects and the high abuse potential of PCP significantly limit the practical therapeutic value of this compound.
The psychotic and ataxic effects associated with PCP appear to be mediated by PCP binding to σ receptors. It has been recognized in the art that compounds that selectively bind to the PCP binding site of the NMDA receptor (relative to the PCP binding site of the σ receptor or other neuronal receptors) might be useful neuroprotective agents. Such compounds can act as selective, non-competitive antagonists of NMDA receptor function. The literature proposes that development of PCP analogs might provide useful therapeutic agents for treatment of neurodegenerative conditions associated with over activation of NMDA-bearing cells such as neurons in neurodegenerative conditions. However, data demonstrating the efficacy of any such analogs or types of analogs for this purpose have been lacking prior to this disclosure.
The present disclosure overcomes those shortcomings by providing NMDA receptor antagonism data for compounds designed based on structure-function analyses of PCP which were undertaken by the present investigators in order to identify potentially efficacious therapeutic agents that inhibit NMDA receptor activity.
PCP has three moieties: a phenyl ring, a 6-membered cycloalkyl ring and a piperidine (cyclic amine) moiety, arranged as shown below:

Many PCP analogs are known and have been described. See, for example, Linders et al., 1993, J. Med. Chem. 36: 2499-2507; Thurkauf et al., 1990, J. Med. Chem. 33: 2211-2215; Johnson, 1985, Ann. Rep. Med. Chem. 24, Chap. 5; Kamenka et al., 1982, J. Med. Chem. 25: 431-435; Kalir et al., 1969, J. Med. Chem. 12: 473-477; Cone et al., 1984, J. Pharmacol. Exp. Ther. 228: 147-153; Manallack et al., 1988, Mol. Pharmacol. 34: 863-879; Bowen et al., 1993, Mol. Neuropharmacol. 3: 117-126; Quirion et al., 1992, Trends Pharmacol. Sci. 13: 85-86; Walker et al., 1990, Pharmacol. Rev. 42: 355-402; Rogawski, 1993, Trends Pharmacol. Sci. 14: 325-331; Brennan, 1996, Chem. Eng. News 74: 41-45; de Costa et al., 1992, J. Med. Chem. 35: 4704-4712; Hays et al., 1993, J. Med. Chem. 36: 654-670; Staley et al., 1996, Psychopharmacology, Berl., 127: 10-18; Keana et al., 1989, Proc. Natl. Acad. Sci. USA 86: 5631-5635; Reynolds et al., 1992, Eur. J. Pharmacol. 226: 53-58; Chen et al., 1992, J. Med. Chem. 35: 1634-1638; Rajdev et al., 1993, Br. J. Pharmacol. 109: 107-112; Reynolds et al., 1990, Adv. Pharmacol. 21: 101-126; and Ortwine, 1994, ACS Satellite Television Seminar, “Molecular Modeling: The Small Molecule Approach,” pp. 47-65.
Adejare and Sun (The 228th ACS National Meeting, Philadelphia, Pa., Aug. 22-26, 2004, Abstract MEDI 67) report the synthesis and chemical characterization of two classes of fluorinated PCP analogs. In one class, the phenyl ring is replaced with a 2-fluorophenyl group, the cycloalkyl group with a bicycloalkyl group, and the amine is variously a free amine, pyrrolidine or piperidine. In the other class, the phenyl moiety is also replaced by a 2-fluorophenyl group and the amine is variously a free amine, pyrrolidine or piperidine. However, in this group, the cycloalkyl group is a cyclopentyl or cyclohexyl group. Although this report speculates that these PCP analogs might act as selective NMDA receptor antagonists, no suggestive or confirming data is provided.
Sun and Adejare (AAPS PharmSci 5: Abstract M1127, October 2003) describe synthesis of nine PCP analogs, each having same bicycloalkyl group, namely a bicyclo[2.2.1]heptyl group. The remainder of the molecules have the phenyl ring as a phenyl, 3-fluorophenyl or 4-fluorophenyl group with the amine moiety being a free amine, pyrrolidine or piperidine. These nine PCP analogs are also speculated to potentially act as selective NMDA receptor antagonists, but again no suggestive or confirming data is provided.
Without structure-function correlations, i.e., without pharmacological or biological data, the selectivity of PCP analogs for NMDA and σ receptors cannot be accurately predicted, nor can potential therapeutic efficacy of such analogs. For example, after assessing the biological activity of some of the PCP analogs described by Adejare and Sun (2004) and Sun and Adejare (2003), it was subsequently discovered by the present investigators that many of the compounds disclosed in those references are toxic and unsuitable for therapeutic use. The present disclosure is based, in part, on the unexpected finding that PCP analogs having more constrained alkyl rings (i.e., those having multiple cyclic alkyl rings) and para-substituted phenyl rings exhibit suitable activity and have significantly less toxicity while exhibiting neuroprotective action. As such, the present disclosure significantly advances the knowledge in this field.